Progenitor endothelial cell capturing with a drug eluting implantable medical device

Abstract

A medical device for implantation into vessels or luminal structures within the body is provided, which stimulates positive blood vessel remodeling. The medical device, such as a stent and a synthetic graft, is coated with a pharmaceutical composition consisting of a controlled-release matrix and one or more pharmaceutical substances for direct delivery of drugs to surrounding tissues. The coating on the medical device further comprises a ligand such as a peptide, an antibody or a small molecule for capturing progenitor endothelial cells in the blood contacting surface of the device for restoring an endothelium at the site of injury. In particular, the drug-coated stents are for use, for example, in balloon angioplasty procedures for preventing or inhibiting restenosis.

What is claimed is: 
     
       1. An implantable medical device having a luminal surface and a coating; wherein the coating comprises (a) one or more layers of a matrix; (b) one or more pharmaceutical substances that inhibit smooth muscle cell proliferation and/or migration, and (c) a ligand attached to the matrix, wherein the ligand is an antibody, an antibody fragment or a combination thereof, and wherein the antibody or antibody fragment specifically binds to a cell surface marker of endothelial progenitor cells and/or endothelial cells and captures circulating endothelial progenitor cells and/or endothelial cells on the luminal surface of the device after implantation of the device. 
     
     
       2. The implantable medical device of  claim 1 , wherein the medical device is a stent, a vascular graft, a synthetic graft, a heart valve, a catheter, a vascular prosthetic filter, a pacemaker, a pacemaker lead, a defibrillator, a patent foramen ovale (PFO) septal closure device, a vascular clip, a vascular aneurysm occluder, a hemodialysis graft, a hemodialysis catheter, an atrioventricular shunt, an aortic aneurysm graft device or components, a venous valve, a sensor, a suture, a vascular anastomosis clip, an indwelling venous or arterial catheter, a vascular sheath and a drug delivery port. 
     
     
       3. The implantable medical device of  claim 1 , wherein the matrix comprises a porous material comprising nanoparticles. 
     
     
       4. The implantable medical device of  claim 3 , wherein the nanoparticles comprise a metal, or a metallic alloy. 
     
     
       5. The implantable medical device of  claim 1 , wherein the cell surface marker is selected from the group consisting of CD133, CD45, CD34, CD31, CD14, CDw90, CD117, VEGFR-1, VEGFR-2, Muc-18 (CD146), CD130, stem cell antigen (Sca-1), stem cell factor 1 (SCF/c-Kit ligand), Tie-2, MHC H-2Kk, HLA-DR, and a combination thereof. 
     
     
       6. The implantable medical device of  claim 1 , wherein the matrix is formed of nanoparticles having porous openings of from about 5 nm to about 5 μm in diameter and the ligand is an antibody, antibody fragments or combinations thereof. 
     
     
       7. The implantable medical device of  claim 1 , wherein the antibody or antibody fragment is anti-CD34 or anti-CD133. 
     
     
       8. The implantable medical device of  claim 1 , wherein said one or more pharmaceutical substance(s) is/are selected from the group consisting of peroxisome proliferator-activated receptor-alpha agonists, peroxisome proliferator-activated receptor-delta agonists, peroxisome proliferator-activated receptor-gamma agonists, calcitonin gene related peptide (o-CGRP), monocyte chemoattractant protein-1, adenosine, prostacyclins, tachykinins, sialokinins, neurokinins, aromatase inhibitors, plasminogen activator, erythropoietin, darbepotin, serine proteinase-1 (SERP-1), metalloproteinases, and a combination thereof. 
     
     
       9. The implantable medical device of  claim 1 , wherein said one or more pharmaceutical substance(s) is/are selected from the group consisting of rapamycin, a rapamycin derivative, everolimus, sirolimus, biolimus, biolimus A-9, paclitaxel, and a combination thereof. 
     
     
       10. A method for treating vascular disease, comprising the step of implanting into a patient in need of treatment an implantable medical device, wherein the medical device has a luminal surface and a coating, wherein the coating comprises (a) one or more layers of a matrix; (b) one or more pharmaceutical substances that inhibit smooth muscle cell proliferation and/or migration, and (c) a ligand attached to the matrix, wherein the ligand is an antibody, an antibody fragment or a combination thereof, wherein the antibody or antibody fragment specifically binds to a cell surface marker of endothelial progenitor cells and/or endothelial cells, and wherein the ligand captures circulating endothelial progenitor cells and/or endothelial cells on the luminal surface of said medical device after implantation into said patient. 
     
     
       11. The method of  claim 10 , wherein the matrix is formed of a porous material comprising nanoparticles. 
     
     
       12. The method of  claim 11 , wherein the nanoparticles comprise a metal, or a metallic alloy. 
     
     
       13. The method of  claim 10 , wherein the cell surface marker is selected from the group consisting of CD133, CD45, CD34, CD31, CD14, CDw90, CD117, HLA-DR, VEGFR-1, VEGFR-2, Muc-18 (CD146), CD130, stem cell antigen (Sca-1), stem cell factor 1 (SCF/c-Kit ligand), Tie-2, and MHC H-2Kk. 
     
     
       14. The method of  claim 10 , wherein the matrix comprises nanoparticles having porous openings of from about 5 nm to about 5 μm in diameter. 
     
     
       15. The method of  claim 10 , wherein the antibody or antibody fragment is anti-CD34 or anti-CD133.